Atherosclerosis is a condition in which abnormal amounts of lipids are deposited in certain arteries, resulting in intimal thickening. The condition manifests itself by circulatory occlusion, principally of the coronary, cerebral and peripheral arteries. Ensuing complications can lead to coronary heart disease, cerebrovascular disease, and some forms of peripheral vascular disease. These conditions are the major causes of death in the United States. It has long been known that there is a relationship between atherosclerosis and high levels of plasma lipids, particularly cholesterol. In fact, hypercholesterolemia is a primary risk factor for coronary heart disease. In humans, more than one-half of total body cholesterol is derived from de novo synthesis.
Many individuals can lower their elevated cholesterol levels by dietary management of the amounts of cholesterol and fat they ingest. However, for patients who require therapeutic intervention for proper management of their serum cholesterol levels, only a few drugs are available, and many of these patients are unable to use these drugs because of the attendant side effects. There is accordingly a need in the art for agents which can lower serum cholesterol levels without giving rise to deleterious side effects.
The present invention is addressed to the aforementioned need in the art, and is premised on the discovery that certain synthetic oxysterols are extremely useful in inhibiting the biosynthesis of cholesterol. While not wishing to be bound by theory, the inventors herein postulate that these new agents act by either inhibiting or down-regulating the levels of hydroxy-methylglutaryl-coenzyme A reductase ("HMG-CoA reductase"), or by inhibiting or down-regulating the levels of low-density lipoprotein ("LDL") receptors, or a combination thereof. The present compounds are surprisingly effective in inhibiting cholesterol biosynthesis; the compounds may also have utility as prophylactic agents for general use against atherosclerosis and coronary heart disease.